# US 10,500,272 B2 · Manufacture of surfactant-containing compositions with enhanced stability

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- Number: US 10,500,272 B2
- Document ID: US10500272B2
- Status: Granted
- Kind: B2
- Application number: 16/299,372
- Filed: 2019-03-12
- Published: 2019-07-11
- Granted: 2019-12-10
- Earliest claimed: 2014-12-02
- Assignees: Novartis AG
- Applicants: Novartis AG
- Inventors: Gottfried Kraus
- Web page: https://patentgrep.com/patent/US10500272B2

## CPC

- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61K 9/107: Emulsions {; Emulsion preconcentrates; Micelles (composition of emulsions A61K47/00)}
- A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53)
- A61K 39/145: Orthomyxoviridae, e.g. influenza virus
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- B01D 71/68: Polysulfones; Polyethersulfones
- C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00)
- A61K 2039/55566: {Emulsions, e.g. Freund's adjuvant, MF59}
- B01D 2325/022: Asymmetric membranes
- B01D 2325/36: Hydrophilic membranes
- C12N 2760/16034: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- B01D: SEPARATION (separating solids from solids by wet methods B03B, B03D; by pneumatic jigs or tables B03B; by other dry methods B07; magnetic or electrostatic separation of solid materials from solid materials or fluids, separation by high-voltage electric fields B03C; centrifuges, vortex apparatus B04; presses per se for squeezing-out liquid from liquid-containing material B30B9/02; treatment of water C02F, e.g. softening by ion-exchange C02F1/42; {arrangements of air intake cleaners in gas turbine plants F02C7/05} ; arrangements or mounting of filters in air-conditioning, air-humidification or ventilation F24F13/28)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Improved methods for the manufacture of pharmaceutical compositions comprising at least one surfactant, involving prefiltration of the surfactant prior to formulation into final products.

## Claims

### Claim 1

A process for preparing an emulsion comprising steps of:
(a) purifying a surfactant by filtering said surfactant through a filter having a pore size between 5-50 μm; and
(b) forming the emulsion by:
i. combining the purified surfactant with an aqueous component and adding an oil component; or
ii. combining the purified surfactant with an oil component and adding an aqueous component.

### Claim 2 (depends on 1)

The process of claim 1, wherein the surfactant is a polymeric surfactant.

### Claim 3 (depends on 2)

The process of claim 2, wherein the polymeric surfactant is polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, t-octylphenoxypolyethoxyethanol, (octylphenoxy)polyethoxyethanol, poloxamers, or polyoxyethylene alkyl ether.

### Claim 4 (depends on 1)

The process of claim 1, wherein the surfactant is polysorbate 80 and step (a) comprises: filtering non-aqueous polysorbate 80 through a polypropylene filter having a pore size between 10-40 μm.

### Claim 5 (depends on 1)

The process of claim 1, wherein the purified surfactant is combined with an aqueous material between steps (a) and (b).

### Claim 6 (depends on 1)

The process of claim 1, wherein the emulsion is an oil-in-water emulsion.

### Claim 7 (depends on 1)

The process of claim 1, wherein the emulsion is a water-in-oil emulsion.

### Claim 8 (depends on 1)

The process of claim 1, wherein the emulsion is a water-in-oil-in-water emulsion.

### Claim 9 (depends on 1)

The process of claim 1, wherein the oil component comprises squalene.

### Claim 10 (depends on 2)

The process of claim 2, wherein the oil component comprises squalene.

### Claim 11 (depends on 1)

The process of claim 1, wherein step (b) comprises homogenization to form a homogenized emulsion.

### Claim 12 (depends on 11)

The process of claim 11, wherein step (b) comprises sterile filtration of the homogenized or microfluidized emulsion.

### Claim 13 (depends on 1)

The process of claim 1, wherein the purified surfactant is a bulk preparation of purified surfactant having a volume of at least 50 litres.

### Claim 14 (depends on 1)

The process of claim 1, wherein the emulsion is a vaccine adjuvant.

### Claim 15 (depends on 1)

The process of claim 1, wherein the emulsion has less than 0.85 ppm acetaldehyde.

### Claim 16 (depends on 1)

The process of claim 1, wherein the emulsion comprises squalene and the emulsion has less than 661 picograms of polychlorinated biphenyls per gram of squalene (toxic equivalent TEQ).

### Claim 17 (depends on 1)

A method for preparing a vaccine composition, comprising preparing an emulsion according to claim 1 and combining the emulsion with an antigen.

### Claim 18 (depends on 1)

A method for preparing a vaccine kit comprising preparing an emulsion according to claim 1 and packaging the emulsion into a kit as a kit component together with an antigen component.

### Claim 19 (depends on 17)

The method of claim 17, wherein the antigen is an influenza virus antigen.

### Claim 20 (depends on 19)

The method of claim 19, wherein the vaccine composition includes about 15 about 10 about 7.5 about 5 about 3.8 about 1.9 or about 1.5 μg of hemagglutinin per influenza virus strain.

### Claim 21 (depends on 18)

The method of claim 18, wherein the antigen is an influenza virus antigen.

### Claim 22 (depends on 21)

The method of claim 21, wherein the vaccine composition includes about 15 μg, about 10 μg, about 7.5 μg, about 5 μg, about 3.8 μg, about 1.9 μg, or about 1.5 μg of hemagglutinin per influenza virus strain.

### Claim 23 (depends on 2)

A method for preparing a pharmaceutical composition comprising preparing an emulsion according to claim 2 and formulating a pharmaceutical composition comprising the emulsion.